Kaposi sarcoma (KS), the most common HIV-associated malignancy worldwide, is attributable to infection with human herpesvirus 8 (HHV-8). In populations in the US and Africa with high prevalence of HIV infection, HHV-8 co-infection is extremely common. The ramifications of HIV and HHV-8 co-infection for the natural history of HIV and HHV-8 associated diseases are unknown. However, it is clear that HIV increases the incidence and severity of KS, and our preliminary data find that HHV-8 infection may also exacerbate the progression of HIV disease. Highly active antiretroviral therapy (HAART) reduces the incidence and severity of KS in the US, but may not be as effective in Africa where the burden of HHV-8 disease is substantially higher and immune reconstitution inflammatory syndrome (IRIS) commonly leads to a worsening of HHV-8-associated disease. Based on previous and ongoing research, our group has developed a conceptual model which posits that: A) among individuals co-infected with HIV and HHV-8, each virus acts synergistically to enhance the other's replication;B) the use of HAART reduces HHV-8 replication in a manner which is both dependent and independent of its effect on HIV replication;C) persons with HHV-8 infection are divided between those with frequent replication in the peripheral blood and at mucosal sites and those without;and D) persistent HHV-8 replication may limit the efficacy of HAART in suppressing HIV replication We propose a prospective cohort study of 350 HIV/HHV-8 co-infected Ugandans initiating HAART to evaluate the following Specific Aims: (1) Determine whether the clinical and virologic manifestations of HIV infection at the time of HAART initiation, and in the 2 years following, impact the suppression of HHV-8 mucosal and peripheral blood replication;(2) Determine whether the virologic characteristics of HHV-8 infection at the time of HAART initiation, and in the 2 years following, impact the suppression of HIV at mucosal and peripheral blood sites;(3) Characterize the frequency and correlates of HHV-8-associated IRIS. PUBLIC HEALTH RELEVANCE: This proposal seeks to understand how HIV and human herpesvirus 8 co-infection may impact the natural history of both HIV and HHV-8 associated disease. Knowledge gained from this proposal may lead to improved strategies for the use of highly active antiretroviral therapy among the majority of HIV-infected individuals worldwide who are HIV and HHV-8 co-infected, better preventative measures and treatments for HIV- associated cancers, and new strategies for increasing the efficacy of HAART in preventing HIV disease progression and transmission.